The present invention relates to compositions useful for the diagnosis and therapy of diseases associated with aberrant expression of the genes encoding the proteins Futrin 1, 2, 3 and/or 4 (=R-Spondin 2, 3, 1 and 4, respectively). These diseases include tumors of e.g. the breast, ovary, liver, uterus, cervix, colon, lung, ovary, rectum, testis, pancreas, bones and skin, as well as diseases involving muscle, bone, lipid and glucose metabolism, and obesity. The present invention also relates to a pharmaceutical composition containing a compound which is capable of modifying (a) the expression of the gene encoding Futrin 1, 2, 3 and/or 4 or (b) the activity of Futrin 1, 2, 3 and/or 4.
The Wnt signal cascade plays a crucial role as regards regulation of survival, proliferation and differentiation of cells during embryogenesis, and in the adult as shown, e.g., in Drosophila, Xenopus and mice (Nusse and Varmus, Cell 69 (1992), 1073-1087). Wnt-genes encode secretory glycoproteins which activate a well characterized signal cascade via a Wnt receptor called “frizzled”.
The Wnt signalling cascade and its components also play an important role in various diseases which makes it desirable to modulate its activity:
i) Cancer
Tumorigenesis represents a complex multistage process in which genetic changes and environmental factors are thought to deregulate the cellular processes that control cell proliferation and differentiation. Several studies indicate that an aberrant Wnt signal cascade is involved in the development of colon cancer, breast cancer and melanoma (Pfeifer, Science, 2 75 (1997), 1752-1753; Polakis, Genes Dev. 14 (2000), 1837-1851). The first gene encoding a protein of the Wnt signal cascade, int-1, was isolated from mouse mammary tumor virus (MMTV) and it could be shown that it is an oncogene. It is thus well established that an aberrant regulation of the activity of Wnt and/or components of the Wnt signal cascade downstream of the Wnt signal, e.g., beta-catenin and APC, are involved in tumorigenesis.ii) Bone DiseaseWnt signals promote bone formation (e.g. Yang, Development, 130 (2003), 1003-15; Fischer, J. Biol. Chem. 277 (2002) 30870-30878). Consistent with this notion, a gain-of-function mutation of the Wnt receptor LRP5 causes high bone disease (Boyden, et al., 346 (2002) N Engl J Med, 1513-21; Little, et al., 70 (2002) Am J Hum Genet, 11-9). Conversely, inactivating mutations in LRP5 leads to osteoporosis-pseudoglioma syndrome in humans (Kato, et al., 157 (2002) J Cell Biol, 303-14; Gong, et al., 107 (2001) Cell, 513-23).iii) Eye DiseaseInactivating mutation in the Wnt receptor LRP5 lead to pseudoglioma in humans and eye malformations in mice (Kato, et al., 157 (2002) J Cell Biol 303-314; Gong, et al., 107 (2001) Cell, 513-523).iv) KidneyAberrant Wnt signalling is involved in renal fibrosis (Surendran, Am J Physiol Renal Physiol 282 (2002) 431-441) and polycystic kidney disease (Saadi-Kheddouci, Oncogene 20 (2001) 5972-5981).v) Lipid and Glucose Metabolism, ObesityDeficiency of the Wnt receptor LRP5 in mice leads to increased plasma cholesterol levels in mice fed a high-fat diet, because of the decreased hepatic clearance of chylomicron remnants. In addition, when fed a normal diet, LRP5-deficient mice show a markedly impaired glucose tolerance (Fujino, et al., 100 (2003) Proc Natl Acad Sci USA, 229-234.) Administration of the LRP5 antagonist Dkk1 to mice reduces glucose uptake in various cell line and decreases fat deposition (WO 02/066509).
It is thus clear from the above that the Wnt signalling pathway is involved in a variety of human diseases. Yet, means for the therapy or diagnosis of diseases associated with a dis-regulated Wnt signal cascade are insufficiently available. Thus, the use of reliable diagnostic molecular markers would be helpful for an understanding of the molecular basis of diseases associated with an aberrant Wnt signal cascade. It can be expected that such markers are also useful for therapy and for the development of novel therapeutic avenues for treatment of Wnt signal cascade dependent diseases, as detailed above.
Thus, the technical problem underlying the present invention is to provide means for diagnosis and therapy of diseases associated with an aberrant Wnt signal cascade.
The solution to said technical problem is achieved by providing the embodiments characterized in the claims.
During the experiments resulting in the present invention four genes, futrin 1, 2, 3 and 4, could be identified the products of which are modulators of the Wnt pathway. Futrin 2 was previously identified as hPWTSR (Chen et al., 29 (2002), Mol. Biol. Rep. 287-292), a protein of before unknown role or function, expressed in numerous cell types. Further, human Futrin 1, 2, 3, and 4 were described as Stem Cell Growth Factor-Like Polypeptides, which are able to promote proliferation of hematopoietic stem cells (WO-A-01/77169; WO-A-01/07611).